Homogeneous solid fusions of particulate mineral nutrients in a continuous rhombic sulfur matrix containing at least about 50 weight percent sulfur are disclosed. These materials are obtained by dispersing throughout a sulfur melt at a temperature of 120.degree. to about 400.degree. C. a nutrient-hydrocarbon comixture containing sufficient hydrocarbon to thoroughly wet all surfaces of the mineral nutrient, preferably sufficient to form a suspension of the nutrient in the hydrocarbon, followed by cooling to form the solid fusion. These materials have particular utility in agronomic applications as soil supplements for supplying both sulfur (as sulfate) and mineral nutrients at a continuous, regulated rate from inexpensive raw materials.

Due to the increasing demands on the agricultural industry, there is a commensurate need for supplementing plant nutrients, either by soil or foliar application. These nutrients include a variety of minerals such as phosphorus, zinc, iron, copper, magnesium, manganese, molybdenum and boron. Elemental sulfur supplies soluble sulfate. It has the further advantage of reducing soil alkalinity.
It is often desirable to supplement soil concentrations of more than one of these nutrients in a single application. Thus it would be beneficial to have a single nutrient combination in an easily handleable form that would not segregate during transport or application.
Obviously, all of the nutrients could be supplied individually; and that procedure has the equally obvious advantage of allowing immediate on-site variation of nutrient concentration. However, it has the disadvantage that all nutrients are not maintained in immediate proximity to each other. In some cases this factor is not particularly significant. However, I have found that bacterial sulfur oxidation creates an acidic environment in the vicinity of the sulfur particles and that this environment can convert insoluble mineral nutrients such as mineral oxides, carbonates and sulfides, to soluble sulfates. This acidification even improves the mobility of nutrients applied as soluble compounds in calcareous soils by reducing the tendency of otherwise mobile compounds to convert immobile hydroxides, oxides, or the like. These nutrients must be made available to the plant roots in a soluble, mobile form to allow their assimilation by the crop.
The acidizing effect of elemental sulfur applied in any reasonable dosages, e.g., 20 to 800 pounds per acre, exists only, or at least to a large extent, in the area adjacent the sulfur particle. Thus, at least in calcareous soils, soil pH will increase with distance from the particle surface. Due to this effect and the beneficial influence of sulfur acidification on nutrient mobility, particularly on the conversion of insoluble, immobile compounds to mobile forms, it would be desirable to assure that all of the applied nutrient is fixed in the immediate vicinity of, and preferably within, the sulfur particle. It is even more desirable that the nutrient compound be evenly distributed throughout the matrix of the sulfur particle to assure gradual nutrient release rather than a slugging effect that would result from alternative procedures such as surface coating.
There are a number of mineral nutrient sources. Some are soluble such as the sulfates, nitrates and complexes with chelating agents, all of which are known in the agricultural industry. Inexpensive nutrients can be obtained as the oxides, sulfides and carbonates, the oxides being particularly preferred due to availability and low cost. However, in an attempt to form homogeneous combinations of these supplements with molten sulfur I discovered that they could not be distributed throughout the sulfur melt even with reasonably severe agitation. While better distribution, if not homogeneous combinations, might be obtained with extremely high shear mixing techniques in some cases, such techniques increase capital cost and operating expense.
Therefore, it is one object of this invention to provide a method for producing homogeneous, solid fusions of inexpensive, finely divided mineral nutrients in a continuous rhombic sulfur matrix. Another object is the provision of an improved continuous process for the formation of such homogeneous solid fusions. Yet another object is the provision of improved, homogeneous solid fusions of inexpensive mineral nutrients dispersed throughout a continuous rhombic sulfur matrix which assure an even, gradual nutrient release from the sulfur particles as a result of gradual, bacterial oxidation. Another object is the provision of methods for producing such mineral-sulfur solid fusions that result in little or no nutrient loss during manufacture, e.g., by leaching by aqueous quench media.
In accordance with one embodiment, homogeneous solid fusions of particulate mineral nutrients dispersed in a continuous rhombic sulfur matrix are obtained by dispersing throughout a sulfur melt a nutrient-hydrocarbon comixture containing at least about 10 weight percent of a finely divided water-insoluble plant nutrient compound and at least about 2 weight percent of a non-polar hydrocarbon. The hydrocarbon concentration must be at least sufficient to completely wet the exterior surfaces of the finely divided nutrient. Mild agitation is sufficient to assure even distribution of the nutrient-hydrocarbon comixture throughout the melt. The resulting suspension is then cooled to a temperature below the melting point to form blocks or particles of the homogeneous, nutrient-sulfur fusion as desired.
The nutrient compounds are selected for their relatively low cost, availability and water insolubility. Water insolubility is particularly desirable in the preferred embodiment which involves comminuting and solidifying the sulfur-nutrient melt by contacting with water. Such nutrients include calcium phosphate and the oxides, sulfides and carbonates of zinc, iron, copper, magnesium, manganese, molybdenum and boron. Of the nutrients other than phosphorus, the oxides are particularly preferred due to their very low solubility, availability and low cost.
To one degree or another, all of these materials suffer from the disadvantage that they can be dispersed in molten sulfur only with considerable difficulty, if at all. Thus the formation of a completely homogeneous distribution of the nutrient compound in the sulfur melt prior to quenching is difficult if not impossible. I have found that this difficulty can be overcome by assuring that all surfaces of the nutrient compound are coated with a non-polar hydrocarbon prior to admixture with the sulfur melt.
The same is true of the insoluble calcium phosphate source. By these methods the phosphate can be easily and uniformly dispersed in molten sulfur in relatively high concentrations, e.g., up to about 50 weight percent. The combinations also have other notable advantages in agricultural use.
Calcium phosphates are widely available as several minerals such as apatite, usually containing fluorine, e.g., fluoro-apatite, some copyrolites and some phosphorites of which significant deposits exist in both this and foreign countries.
Available, i.e., soluble phosphate, is usually derived from insoluble calcium phosphate by dissolving the calcium phosphate in sulfuric acid to release phosphoric acid and calcium sulfate (gypsum) both of which have agronomic value. The product acid, generally known as wet-process phosphoric acid, is a widely used industrial and agricultural commodity. The usual manufacturing methods require the preliminary manufacture of sulfuric acid and, in the great majority, if not all cases, require separation of the dilute phosphoric acid from insoluble calcium sulfate byproduct.
The most widely used sulfuric acid manufacturing procedure involves sulfur oxidation to sulfur dioxide which is then converted to sulfur trioxide over a vanadium catalyst followed by hydrolysis to the acid. Once obtained, this acid is used to convert insoluble calcium phosphate (from fluoroapatite or otherwise) to insoluble calcium sulfate and dilute phosphoric acid. The phosphoric acid is then recovered in the supernatent phase and concentrated by conventional procedures. Calcium sulfate is recovered by filtration. Both of these materials can be used as soil additives.
I have found that the embodiment of this invention employing crude phosphate rock eliminates all of the manufacturing steps involved in the conventional production of calcium sulfate and phosphoric acid referred to above. It does so in a very effective manner in that the resulting sulfur fusions, being homogeneous, assure continuous availability of soluble phosphate and sulfur as calcium sulfate at a rate dependent only on the rate of sulfur-active bacterial action.
In this respect another advantage of this invention is that the activity of heterotropic thiobacillae is increased due to the presence of hydrocarbon in the sulfur matrix. The hydrocarbon provides a carbon source for the bacteria thereby accelerating their growth and consequently the conversion of sulfur to sulfuric acid. By this technique the amount and type of hydrocarbon can be controlled or selected to control the rate of phosphate and sulfur release. All of these things are accomplished with very inexpensive, readily available minerals, e.g., elemental sulfur and crude phosphate rock.
Accordingly, the methods and compositions of this invention have several significant advantages over those known to the prior art. They allow for the use of inexpensive readily available water-insoluble oxides, sulfides and carbonates. They require much less agitation or shear to obtain adequate nutrient distribution than is the case with alternative methods. They result in easily obtained, homogeneous, macronutrient dispersions in both the sulfur melt and product matrix. They minimize or completely eliminate nutrient loss during formulation or shipment, and they do not so weaken the product particles as to make them friable in transport or use.
On the contrary, I have found that the hydrocarbon results in several advantages other than nutrient dispersibility. The product particles, when formed as such, are more fluid than are particles not containing hydrocarbon. They have significantly less tendency to dust or autoignite during transport or use and they do not bridge and plug transportation and application equipment. Product homogeneity assures more uniform nutrient release. The hydrocarbon also accelerates heterotrophic bacteria activity and therefore increases nutrient release rate. Due to the low shear mixing made possible by these methods, they are readily adaptable to continuous, low shear formulation procedures.
The preferred metal nutrients are zinc, iron, copper, magnesium, manganese, molybdenum and boron in the form of the corresponding oxides, carbonates and sulfides. The oxides are particularly preferred for the reason discussed above. I have also found that these materials, particularly the oxides, can be compounded into very concentrated hydrocarbon comixtures to produce fluid suspensions containing up to 75 weight percent of the metal oxide. I have also discovered that such high concentrations, e.g., above 30 weight percent of the metal oxide, particularly the oxides of zinc and iron, can be obtained only under anhydrous conditions. Accordingly, oxides containing water should be heated to a temperature sufficient to drive off water, e.g., at least about 110.degree., preferably at least about 120.degree. C., for a period sufficient to produce an anhydrous powder. Care should also be taken to assure that the oil is substantially anhydrous so that the total composition, i.e., metal oxide and oil, contains less than 0.5 weight percent water. Under these conditions, relatively stable nutrient-hydrocarbon suspensions can be obtained with only minor agitation and can be maintained in that form with only periodic agitation.
This characteristic greatly facilitates nutrient-sulfur mixing in either batch or continuous operations. It allows for metering of the hydrocarbon-nutrient suspension directly into the melt at a controlled rate or in otherwise controlled amounts to provide a composition having the desired nutrient content. Furthermore, the availability of high nutrient content suspensions also minimizes the amount of hydrocarbon required to transport the desired amount of nutrient in a fluid form, when reduced hydrocarbon concentrations are desired. Similar suspensions can be obtained with the calcium phosphate sources referred to above.
The several components should be mixed in proportions sufficient to assure a product fusion containing at least about 50, preferably at least about 70, weight percent rhombic sulfur. The remainder of the product can comprise hydrocarbon and nutrient compound and/or other solid components such as fillers, clays and the like, as desired. These compositions can contain 1 to about 50, preferably 1 to about 20, weight percent of the hydrocarbon-nutrient comixture.
The hydrocarbon-nutrient suspension can contain as little as one percent nutrient but usually contains at least about 5, often at least about 10, and preferably about 10 to about 75 weight percent nutrient compound.
Better nutrient-hydrocarbon distributions, more stable comixture suspensions, and better product homogeneity are obtained when the nutrient compounds are added as finely divided particles. These are usually characterized as particles passing 50 mesh and preferably passing 100 U.S. Standard screen.
The hydrocarbon-nutrient combination can be added either as a nutrient-hydrocarbon suspension or as the finely divided solids containing sufficient hydrocarbon to completely coat all particle surfaces. Thus, the comixture should contain at least about 2 weight percent, preferably 30 to 95 weight percent hydrocarbon. The fluid suspensions containing at least about 30 weight percent hydrocarbon are presently preferred, particularly in continuous processes.
Due to the characteristics of these hydrocarbon-nutrient compound comixtures, they can be evenly distributed throughout the sulfur melt to form a homogeneous distribution under very low shear conditions, at least as compared to the shear rates required to obtain homogeneity by other procedures. For instance, homogeneous compositions can be obtained at the shear rate existing in turbulent pipeline flow within a reasonable period of time, i.e., within 10 seconds or less. Thus, adequate mixing can be obtained at shear rates corresponding to a linear flow velocity only 10 percent above the maximum laminar flow velocity in a pipeline. The optimum amount of shear and time required for any operation can be easily determined by testing the design composition at several shear rates and times, and selecting the best combination by interpolation.
The nutrient-hydrocarbon comixture can be added to the sulfur melt at a temperature of 120.degree. to about 400.degree. C., preferably 120.degree. to about 250.degree. C. by any one of several well-known procedures. However, in both batch and continuous operations it is presently preferred to meter a fluid suspension of the comixture into the sulfur melt. This procedure facilitates more accurate composition control and leads to homogeneous products with only minor agitation of the sulfur-comix combination. It is particularly adaptable to continuous operations in which the comixture and sulfur melt are continuously blended such as in an in-line mixer. Thus the sulfur melt can be continuously transferred from a sulfur melt reservoir or other container and passed by pumps or under pressure into admixture with the nutrient-hydrocarbon comixture which itself is continuously metered from a comix container. The container is preferably provided with agitation means for maintaining an even suspension of the nutrient compound and hydrocarbon prior to combination with the sulfur melt. These two streams are continuously mixed by any one of numerous known in-line mixers, surge tanks, or the like. The combination is then cooled or quenched to form the homogeneous fusion.
The hydrocarbons are preferably liquid at ambient conditions or, more appropriately, the temperature at which the nutrient compound-hydrocarbon comixture is formed. If this temperature is elevated it is essential only that the hydrocarbon be fluid at that temperature to allow adequate coating and mixing of the two components. The hydrocarbons should have a boiling point below the temperature at which the comixture is introduced to the sulfur melt to avoid flashing and hydrocarbon vapor evolution in the mixing apparatus.
Suitable hydrocarbons include virgin or partially refined crudes or synthetic crudes, e.g., derived from coal, oil shale or other origins of natural or synthetic paraffins, aromatics and/or alkyl aromatics. Illustrative are paraffin waxes, gas oils, crude oils, reduced crude oil residuum, naphtha, diesel oil, fuel oil, light and heavy gas oils, kerosene, jet fuel, 80 to 300 neutral oils, paraffin waxes, hydrocarbon homo- or hetero-polymer oils, waxes or thermoplastics such as polyolefins, polystyrene and the like.
The hydrocarbons should be non-polar and non-reactive with sulfur or other components of the composition at melt temperatures. They are preferably paraffinic, aromatic or alkyl aromatic, or combinations of these. From the standpoint of reactivity and toxicity to both plants and sulfur-active bacteria, the hydrocarbons preferably contain, at most, only minor amounts of olefins, alkynes, alkenyl aromatics or compounds containing reactive or toxic functional groups such as hydroxyl, amino, ether, aldo, keto or carboxyl groups, or the like. However, this exclusion does not apply to most halogenated hydrocarbons which are generally unreactive, at least at the lower melt temperatures within the above ranges. Aromatics are somewhat more refractive to sulfur-active bacteria than are paraffinic hydrocarbons. Accordingly, paraffins or compositions consisting primarily of paraffins are particularly preferred for agronomic use.
These methods do not require surfactants to obtain homogeneous distribution of the comixture in the sulfur melt. In fact, such surfactants are preferably avoided at least in most applications due to their reactivity at melt temperatures and/or their toxicity or refractiveness to sulfur-active bacteria.
Moreover, surfactants would be largely wasted in the preferred particle-forming techniques which involve quenching and subdividing the sulfur-comix blend by contacting with liquid water under high shear conditions. At least some of the surfactant would be abstracted from the sulfur phase under these conditions and surfactant removal unavoidably results in hydrocarbon leaching from the sulfur matrix.
The melt can be cooled and solidified, and, if desired, can be comminuted by any one of several procedures. I have found that these melt blends have certain advantages over other formulations in water quenching systems. Very little, if any, hydrocarbon or nutrient is lost to the water phase. Thus the melt can be cooled into blocks and crushed to the desired particle size or it can be air cooled by conventional methods, e.g., by prilling.
Particularly preferred methods involve water quenching by any one of several techniques. The melt can be sprayed into a standing or agitated aqueous quench in which case particle size can be regulated by spray size and agitation severity. Other methods involve pouring a melt into an agitated aqueous quench, in which case particle size is determined primarily by agitation severity.
A particularly preferred method is disclosed in my U.S. Pat. Nos. 3,637,351, 3,769,378 and 3,830,631, incorporated herein by reference. Briefly, these methods involve contacting a high velocity water spray with a high velocity spray of the homogeneous sulfur-hydrocarbon melt to form a highly turbulent intersection zone of the two sprays in which the melt is simultaneously subdivided and quenched into the porous particles similar to those described in the noted patents.
Whichever method is used, it is often desirable to obtain particles having diameters of about one inch or less, usually about one-half inch or less. The methods of my abovementioned U.S. Patents can produce particles having diameters of about 0.02 to about 0.11 inch, and bulk densities below about 1.9, generally below about 1.3, preferably about 0.9 to about 1.3 grams per cc. They are further characterized by porosities of at least about 0.04, generally about 0.04 to about 0.15 cc's per gram, and internal surface areas of at least about 20, preferably between about 30 and about 100 square meters per gram.


A liposome-capsule dosage unit system for the delivery of a biologically active material is formed by encapsulating a biologically active materials in liposomes and then placing the liposome encapsulated material into a capsule. The capsule is typically a soft gel capsule or a two piece capsule capable of tolerating a certain amount of water. A less water tolerant capsule can be employed if the liposomes are dehydrated prior to placement within the capsule. Biologically active material include drugs, nutritional supplements, vitamins, minerals, enzymes, hormones, proteins and polypeptides. The system is especially suited for the delivery of materials with poor oral solubility, materials that are not absorbed or are poorly absorbed from the gastrointestinal tract, and materials that have conventionally been given by an invasive route. The system can be administered orally, intra-occularly, intranasally, rectally, or vaginally.

1. Field of Invention
The invention generally relates to the field of liposome based drug delivery systems.
2. Description of Background Art
The therapeutic effect of an administered substance is usually directly related to the quantity and rate ate which the substance reaches the bloodstream. There are many factors that affect the ability of the substance to reach the systemic circulation including; the site of entry into the body, the physical form of the substance, the design of the formulation of the product, various physicochemical properties of the compound and the excipients, and control and maintenance of the location of the substance at the proper absorption site.
Oral delivery of a therapeutic substance is the most common form of delivery today because of convenience and ease of administration, however, it is not the most reliable route of administration and can often be inefficient and erratic. Factors that influence the absorption, and thus the ability of the substance to reach the bloodstream, of an orally administered substance are related to the physicochemical properties or the substance, the physiologic factors in the gastrointestinal tract and the variables in the dosage form. Conventional oral dosage forms consist of solutions, suspensions, powders, two-piece gelatin capsules, soft gelatin capsules, compressed tablets, and coated tablets. It is generally the case that gastrointestinal absorption is most rapid with solutions and progressively slower as you move toward coated tablets in the above continuum. Liquid dosage forms are generally much faster absorbed than solid forms because dissolution is not a rate determining step in the absorption process.
It has long been the idealized object of drug delivery technology to design a dosage form that optimizes effectiveness, maximizes drug reliability and maximizes safety of the delivered compound. Oral dosage forms began to become optimized in the late 1940""s and early 1950""s when sustained-release technology appeared on the pharmaceutical scene. The principle benefit of this new type of delivery system was to improve drug performance by increasing the duration of drug action and reducing the dosing interval required to achieve a therapeutic effect. Controlled-drug delivery technology, a new concept for improving drug efficacy was developed in the late 1960""s. The principle benefit of this technology is to control the rate of dissolution from the solid dosage form to enhance bioavailability, improve safety, and decrease the dosing interval. Within the last twenty years a newer concept in oral drug delivery technology has been developed and is referred to as a therapeutic system. The essential component of the therapeutic system is the incorporation of advanced engineering controls that release drug from the dosage form at appropriate times in response to stimuli, e.g., preprogrammed wax matrix.
Capsules are a convenient and popular solid dosage form used for drugs, vitamins and nutritional supplements worldwide. The drug substance is enclosed within gelatin walls of the capsule, which can be either a two piece hard shell or a soft shell (also known as the soft elastic capsule). The soft elastic capsule (SEC) is a soft, globular, gelatin shell somewhat thicker than that of hard gelatin capsules. The gelatin is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The greatest advantage of soft gel capsule over two piece gelatin capsules is that soft gels can encapsulate liquids, semiliquids, and pastes due to the manufacturing process which hermetically seals the two halves together. There are several manufacturing processes by which soft gel capsules are made, those include the plate process, the rotary die process, the Norton capsule machine and Accogel, or Stern machine. A newer technology allows a two-piece gelatin capsule to tolerate liquids, semiliquids and pastes by sealing the upper and lower pieces together to prevent leakage of encapsulated material.
Liposomes are microscopic, three-dimensional lipid vesicles, made up of a phospholipid bilayer membrane that surrounds and separate an aqueous compartment. The discovery of liposomes has been credited to Alec Bangham, a British biologist and physician, who first described swollen lipid particles in the early 1960""s. (Bangham A., et al, J. Mol Biol., 13, 238, 1965). However there is evidence of the observation of multilamellar liposomes dating back to 1911. (Lasic, D., Liposomes, 1993). Two decades after Bangham and his colleagues described their discovery the field of liposome science began to take hold, and the pharmaceutical and pharmacological rational that justifies the use of liposomes as drug carriers was being put into practice. Today, the medical applications of liposomes range widely from systemic anticancer therapy to enhancing topical anesthesia and gene delivery.
The use of liposomes orally first begin in the mid 1970""s. The attributes of phospholipid based liposomes, e.g., well organized structures able to encapsulate a variety of compounds, with an excellent safety profile, were well known at the time. Medical researchers believed that this would be an ideal application to potentially enhance gastrointestinal absorption, protect the encapsulated ingredient from metabolic degradation and perhaps release the encapsulate slowly, thus providing a form of sustained release. Early studies showed that liposome encapsulated drugs were better absorbed than non-liposome encapsulated or xe2x80x9cfreexe2x80x9d drug. In addition to drug molecules, proteins, peptides and enzymes were delivered orally with liposomes. In an attempt to develop an oral treatment for hemophilia with blood clotting factor VIII, a novel technique was developed which made possible high-yield entrapment of Factor VIII in a liposome. (Gregoridias, G. et al., J. Microencap., 1(1):33-45,1984). Liposomal encapsulated Factor VIII was administered to patients orally and was absorbed from the intestines. (Sakuragawa N., Thrombosis Research 38(6):681-5, 1985). Early enthusiasm with liposome encapsulated insulin showed that small but significant amount of insulin could reach the circulation (Woodly, J F, Critical Rev Ther. Drug Carrier Sys. 2(1):1-18, 1985). Significant antibody response was elicited after oral administration of liposome-entrapped snake venom (enzymes and peptides) compared to no response from free venom. (New, R R, Toxicon. 23(2):215-9, 1985).
More recently, feasibility of oral liposomes for a variety of therapeutic uses has been demonstrated. Increased bioavailability of liposomally encapsulated superoxide dismutase (Regnault C., et al, Biopharm and Drug Disp 17,165-174, 1996) a potent antioxidant used in the treatment of radiation-induced fibrosis, which is poorly absorbed orally, from 14% (free) to 57% with liposomes with ceramides. Hypocalcemia was observed 1 h after the administration of liposomes loaded with 1 mg of calcitonin. (Arien a., et al, Pharm Research 12(9):1289-1292, 1995). This result was surprising because liposomes were presumed to be unstable against the action of bile salts, however they were able to partially protect the peptide from enzymatic degradation. In another study, recombinant human erythropoietin (Epo), used to treat renal anemia, was encapsulated in liposomes. Bioavailability of oral Epo is poor because it is a protein and broken down in the GI tract by proteolytic enzymes. Absorption and a long pharmacological effect and lag were observed, suggesting that liposomes were trapped in a site before entering the bloodstream, and eliciting a sustained release effect. (Maitani Y., J Pharm Sc 85(4):440-445, 1996).
The pharmaceutical related problems associated with administering liposomes orally are: 1) pH of the stomach, 2) bile salts and 3) digestive enzymes, primarily lipases. The unbuffered pH of the stomach can range from 1.5 to 2.5 and causes chemical instability of the liposome membrane surface.
Bile salts act as detergents and cause instability of the liposome bilayer by emulsification. Upon exposure to lipases and other enzymes, the polar head groups or the acyl chains of the phospholipids can be cleaved and thus rupture the liposome vesicle.
Although certain chemical and stearic modifications can be made to liposomes to help stability, the incorporation of a fluid liposome dispersion into a gelatin based capsule can improve stability, provide a convenient dosage form, and assist in sustained release characteristics of the liposome. The present invention broadly relates to a novel delivery system for biologically active material whereby the biologically active material is encapsulated into liposomes or formulated as a preliposome formulation and then put into a capsule. The capsule can be a soft gel capsule capable of tolerating a certain amount of water, a two piece capsule capable of tolerating a certain amount of water or a two piece capsule where the liposomes are preformed then dehydrated. Biologically active material in this invention can be, but is not limited to, drugs, nutritional supplements, vitamins, minerals, enzymes, hormones proteins and polypeptides.
The delivery system of the invention is especially suitable for 1) biologically active materials with poor oral solubility, e.g. morphine, acyclovir, propanolol, fluoxetine, 2) newly discovered drugs, proteins and peptides that are not absorbed or are poorly absorbed from the gastrointestinal tract, and 3) drugs, proteins, hormones and nutrients that can not be absorbed from the GI tract and have to be given by an invasive route such as injection or nasal inhalation, e.g. Vitamin B12, calcitonin, insulin, erthropoietin, superoxide dismutase.
The liposome-capsule unit containing biologically encapsulated material can be taken in addition to orally, used for topical unit-of-use application, or other routes of application such as intra-occular, intranasal, rectal, or vaginal.
The liposomes in this invention are comprised of any bilayer forming lipid, which includes phospholipids, sphingolipids, glycosphingolipids, and ceramides. The typical size range of the lipsomes is 20 nm-1000 nm. These liposomes can be rehydrated, dehydrated, partially hydrated or fully hydrated. It is also possible to employ a preliposome formulation as the liposome encapsulated biologically active material (liposome-drug complex). This formulation is composed of the biologically active material, phospholipids and cholesterol, and upon contact with water, forms liposomes. The liposomes can be mechanically stabilized using certain phospholipids, e.g. phospholipon 90H, and cholesterol at an optimum molar ratio of 2:1. The optimum ratio is expected to vary with the specific phospholipid selected. This stability can protect the liposome from GI degradation.
Gelatin capsules have a lower tolerance to water on their interior and exterior. The usual water tolerance for a soft gel capsule is 10% on the interior. The concentration of water in a liposome formulation can range from 60-90% water. An essential component of the present invention is the formulation of a liposome with a relatively small amount of water, in the range of 5-10%. By making the liposome in a low aqueous system, the liposome is able to encapsulate the biologically active material and the exposure of water to the inside lining of the capsule is limited. The concentration of water should not exceed that of the tolerance of the capsule for which it is intended. The preferred capsule for this invention is one that can tolerate water in the 15-20% range.
The capsulation of liposomes into a gelatin shell improves the stability of the liposome because it is protected from exposure to the air and thus oxidation. This increases the shelf life of the product. Capsulation will also initially protect the liposome-drug complex from the low pH of the stomach, emulsification from bile salts and degradation of the liposomes and the drug substance by digestive enzymes. This protection can be further enhanced when the outer shell of the capsule is coated with a polymer like hydroxyethylmethyl cellulose propylethyl acetate, or hydroxypropylmethylcellulose propylethyl thallate.
In the past, all administration of oral liposomes have been as a liquid, given by intubation directly into the small intestine, to the back of the throat by a gavage syringe or by dropper directly into the mouth. These are very impractical ways of administering therapeutic agents because they can be messy, provide an inaccurate dose, and are difficult for patients to handle. In addition many biologically active ingredients have a bitter, astringent and unpleasant taste that is unpalatable and difficult to mask. Liposomes in a capsule dosage form provide a convenient, easy to manage unit-of-use which can be more easily handled by the patient than the usual liquid form of a liposome preparation. An easy to take dosage form, such as a capsule, leads to increased compliance by the patient. Noncompliance is disturbingly common. Over one-half of the 1.6 billion prescriptions written annually in the U.S. are taken incorrectly, and 30-50% of the prescribed medications fail to produce their intended results. The economic consequences of medication noncompliance is in excess of $100 billion annually. A significant barrier to compliance is regimen complexity. Reduction of regimen complexity includes use of convenient dosing formulations. It is estimated that 50% of the American population don""t like taking oral liquids. By administering a liposome in a capsule, certain compliance issues are overcome. There has been very little discussion or development of an oral dosage form for liposomes up until now and there are no commercial oral liposome dosage forms available.
The gel caps best used for this invention range in size and shape. The various shapes include, but are not limited to, oval, oblong, cylindrical, round and torpedo shaped. Size of soft elastic capsules is measured by the amount of liquid that can fit into the capsule. The size range of soft gel capsules in this invention is 0.045 cc (0.75 minims) to 5 cc (81.2 minims). The typical size range of two piece capsules is from 600 mg to 30 mg; these capsules are numbered from 000, the largest, to 5, the smallest.


A deal feed system for passing deal tickets to back office systems comprises a deal feed contributor which receives tickets from trades on a plurality of trading systems on a plurality of trading floors, a database for storing the tickets, and a distributor for passing the tickets to back office systems. Virtual deal codes are defined to which a plurality of real deal codes map. The virtual deal codes to which a ticket relates is stored in a table with a reference to the stored ticket. A deal code table is updated with the range of the virtual deal code and the update transmitted to the bank office systems and to traders.

Financial institutions trade many different instruments using many different trading systems. In addition, an institution may have many different trading floors, sometimes located in different countries. In the context of the foreign exchange spot market (FX spot), traders use two main trading system providers, EBS (provided by EBS Dealing Resources Inc.) and Reuters (provided by Reuters plc). These two systems operate completely independently of each other and, when a trade is completed, produce deal tickets which are sent to the back office systems of the counterparties to the deals. Deal tickets are proof that a deal has been entered into by two counterparties and are the means used by the banks to settle with counterparties. Deal tickets also allow reconciliation in the event of any doubt or dispute over a trade. The deal ticket will include an identification of the parties and the deal code: a combination of a bank identifier and a trading system identifier; together with details of the trades such as which party acted as maker and taker, the buy/sell price, the currency and the amount. All counterparties trading on systems such as the Reuters and EBS systems mentioned above are allocated a four letter deal code. This may be a unique code for the bank, in the case of smaller institutions, or may identify a particular trading floor within a bank. The deal tickets further are required to identify the trading system to which they relate and are supplied over a physically separate feed for each trading system on each floor. The feed is in one of a number of established formats. For example, feeds from a Reuters system are in Reuters TOF (Ticket Output Feed) & TOF over 18 format, whereas EBS deals are in ASI (Automated System Interface) format. A bank that trades in the FX markets only using Reuters Dealing 3000 (combined anonymous matching and direct dealing system) and EBS spot matching and EBS Trader Direct Dealing for its foreign exchange products will therefore require three separate deal feed lines for each trading floor. However, large banks will have many trading floors and the back office systems will have cabling for each trading system operated by each trading floor which may include systems trading many other products. The amount of cabling required is extremely inconvenient and extremely expensive. For example, the Reuters TOF protocol requires a separate serial line for each deal code/trading system combination. An attempt to reduce the cabling requirement at back offices has been made by OCL (Options Computers Limited) who provide a product under the trademark DealHub. DealHub is a physical interface which receives inputs from all trading floors and provides a single output to the back office systems. DealHub provides separate servers for both EBS and Reuters Deals and can concatenate multiple input feeds from each system into a single data flow. The servers continuously monitor the data flow from the Reuters TOF and EBS ASI feeds respectively and convert the raw data into data records suitable for trader and back office applications. The DealHub system is useful for reducing the amount of physical cabling required to provide deal related data to back office systems. However, it still requires inputs from all the trading systems operated by all the trading floors of a bank and considerable investment in DealHub hardware and software.
The present invention aims to simplify greatly the provision of deal tickets from trading systems to back office systems. In its broadest form, the invention provides a single deal code for all systems operated by all trading floors of an institution. This code is a virtual deal code to which all real trading floor/trading system codes are attached as children. It can be processed on a single line eliminating the need for separate cabling for each trading floor deal code/trading system combination.
Embodiments of the invention have the advantage that the need for individual cabling from each system operated by each trading floor is avoided. Alternatively, the need for an interface accepting inputs from each trading system on each trading floor, as discussed above, is avoided. Embodiments of the invention greatly simplify the provision of deal tickets to back office systems and so greatly reduce the costs to financial institutions and to trading system providers.
Embodiments of the invention also have the advantage that clients can receive a single range of sequence numbers for deal tickets from different trading systems and or deal codes. This avoids the need for reconciliation by back office systems.
More specifically, the invention provides a method of distributing deal information relating to trades conducted by trading floors on trading systems, each trading floor having a deal code unique to the floor and the system on which the trade is made, the method comprising: defining a virtual deal code to which deal codes of a plurality of trading floors and/or trading systems map, the virtual deal code having an associated deal range.
The invention also provides a system for transmission of deal information relating to trades conducted by trading floors on trading systems to back office systems, wherein deal information is passed from the trading system to a deal feed system, the deal feed system comprising means for defining virtual deal codes to which deal codes of a plurality of trading floors and/or trading systems map, the virtual deal codes each having an associated deal range.
Preferably deal information is transmitted to a virtual deal code within the deal range of that virtual deal code.
Preferably, deal tickets are received from a trading system at the contributor of a deal feed system. The deal tickets include a deal code which identifies the sending trading floor and the trading system on which the deal was conducted. A virtual deal code which maps on to the deal code of the received deal ticket is retrieved and the deal ticket is stored with a reference to the virtual deal code.
Preferably, the deal tickets are stored in a deal ticket table at a database. This database also includes a virtual deal ticket table and a deal code table. A reference to the deal ticket is stored in the virtual deal ticket table with the virtual deal code, and the deal code table is updated to be within the range of the virtual deal code. The updates to the deal code table are distributed to back office systems under the virtual deal codes. This may be via a single socket or serial connection.
Preferably the virtual deal code is configured similarly to a real deal code and includes a virtual trading system name and a virtual deal code name.
In one preferred embodiment of the invention a deal feed system comprises a contributor for receiving deal tickets, a distributor for distribution of deal information to back office systems and a database. The database has a deal ticket table which stores the deal tickets, a deal code table referenced to the deal ticket table for storing the deal code to which the ticket relates and a leg table for storing leg information. Additionally a virtual deal ticket table stores a virtual deal code with a reference to the ticket in the ticket table, together with an RSN number within the range of the virtual deal code. The deal code table for the ticket is updated so that the deal range is that of the virtual deal code. A virtual deal code is a label which references a number of actual deal codes, each of which comprises a trading floor identifier and a trading system identifier. When a deal ticket is received by the deal feed system, the system looks for a virtual deal code to which that deal code maps.
Embodiments of the invention have the advantage that deal tickets from a number of different trading systems on a number of different trading floors can be sent to back office systems via a single socket or serial connection. This avoids the need for large numbers of parallel connections required by prior art systems, making processing at the back office more simple and greatly reducing infrastructure costs.
The invention contemplates the use of a super or virtual deal code which encompasses all trading systems used by all trading systems of an institution. On the face of it, a simple solution to the problem addressed would be to use a simple single adapter. However, this solution is unable to provide a dynamic reproducible range that combines several Trading System/Deal codes together. An adapter making such a combination into a single logical deal code must store the reference originally presented to the back office systems so that the same ticket is returned if the client ever asks for it again. Thus, any simple adapter that interfaces with a deal feed system will require an additional database to store the references and the simple adapter becomes an expensive resource. Clearly this is undesirable.
FIG. 1 illustrates a virtual deal code embodying the principles of the invention. A virtual deal code is a super deal code that, logically, sits above all the real deal codes used by a bank's trading floors for all its trading systems. Thus, the virtual deal code is a label that is defined along with a set of real trading system/deal codes. In FIG. 1 the virtual deal code label is MyBankName/MYVIRDCI, 10 which represents a set of four real deal codes from two trading floors EBSA and EBSB. Each trading floor operates EBS trader™, the conversational EX trading system operated by EBS, and EBS spot, the anonymous FX spot matching system operated by EBS. Thus there are four codes, each comprising the system and the floor: EBSTrader/EBSA 12; EBSTrader/EBSB, 14; SPOT/EBSA 16; and SPOT/EBSB 18.
FIG. 2 shows a schematic view of how a deal feed system communicates with a trading system and customers. The trading system exchanges electronic messages with trading system clients 42 in known manner via a trading system server 40, shown in this case as being via the Internet 44. This is not necessarily the case. For example the EBS Trader® conversational dealing system communicates between clients 42 and server 40 via the Internet, whereas the EBS spot matching system mentioned above communicates via a dedicated communication network.
The exchange of messages between trading system clients 42 and server 40 results in deals being completed.
Details of these deals, for example the parties, the deal amount, currency, settlement date etc. are passed by the trading system to the deal feed system 46. In the embodiment shown, the system is a client-server system with a central server 48 receiving completed trade data from the trading system server and turning that data into deal tickets which it distributes to the appropriate deal feed clients 50 via the Internet. Again, the system need not be Internet based. For any given deal there will be a maker and a taker and the deal ticket must be sent to both parties. The deal feed clients send the received deal tickets to their back office systems for settlement. The tickets can be retrieved either from the local clients or the deal feed server in case of any dispute as to the terms of a completed deal.
FIG. 3 shows the deal feed client in more detail. The client may be a conventional workstation typically running an operating system such as Windows NT®. It is connected to the Internet for communication with the deal feed server 48 via a conventional network access connection 52 and has output to a printer 54 for printing deal tickets, via a serial, parallel or USB cable; and to the back office system 56 using one of the TOF, ASI or TOF over IP protocols. Both TOF and ASI require a serial connection 58 whereas TOF over IP requires a network connection to a hub 60 and then a connection into the back office system 56. Both TOF over IP and TOF/ASI are shown in the Figures but it will be understood that a given institution may not require all the variants.
FIG. 4 shows a conventional known deal feed system used to feed deal tickets from a trading system, in this case the EBS Trader system at trading floor EBSA. The system comprises three main components on both the server and client sides: a deal feed Contributor 22 retrieves deal tickets, in this case from EBSTrader/EBSA. This may be performed on the client or on the server via an input adapter. The deal feed contributor may retrieve deal tickets from a number of sources. The second component is a deal feed Database 24 which stores deal feed tickets in a number of tables. A ticket table 26 holds the common ticket details; a leg table 28 holds leg information; and a deal code table 30 holds the deal range for EBSTrader/EBSA and is incremented each time a deal ticket is retrieved from that code. The third component is a deal feed distributor 32 that, on the server side, feeds deal feed tickets to the deal feed clients of the parties to the deal. Thus, a ticket is sent to EBS Trader/EBSA and to the counterparty to the trade the deal feed distributor takes its input from the deal feed contributor 22 and the deal feed database 24. On the client side the deal feed distributor output is the TDF/ASI or TOF over IP output and the printer output.
The mirroring of the architecture on the server and client sides is shown in FIG. 5.
The deal feed system provides storage and real-time notifications of new deal tickets as follows. When a deal is performed, say at EBSTrader/EBSA, the contributor 22 retrieves the ticket either on the client or the server. The deal is sent to the database 24 where common ticket details are written to the ticket table 26, leg information is written to the leg table 28 and the deal range for EBSTrader/EBSA is incremented in the Deal Code Table 30.
The Deal Feed Distributor is then informed of the updates to both the EBSTrader/EBSA and local deal ranges in real time and the deal distributor 32 then informs any clients subscribed to EBSTrader/EBSA and locally subscribed clients of the updates to the deal ranges.
This operation will now be described in more detail with reference to FIGS. 6 and 7 which show, respectively, how the deal feed contributor and distributor handle tickets. The deal feed contributor 22 connects to a client, which may be a trading system outputting deal tickets, or the deal feed server sending tickets to a deal feed client. The client then contributes tickets into the database, the contributor sends an acknowledgement response whereupon the client disconnects from the contributor.
As shown in FIG. 6, at step 70, the contributor client sends a contribute ticket message to the deal feed contributor 22. At the contributor, a contribution thread checks the message. At step 72, a validated ContributeTicket message is placed on a contribution queue. The messages on this queue will include the trading system 10, deal code, and originator ID as well as the ticket structure. At step 74 a storage thread takes tickets out of the contribution queue and at step 76 attempts to store them in the database 24 via an interface. If the ticket is stored successfully it will be allocated an RSN at step 78 or, if not, an error message will be returned. At step 80 the storage results are placed on an acknowledgement queue and at step 82 a response thread takes tickets from the acknowledgement queue and, if they have an RSN, at step 84, sends a contribution acknowledgement message back to the ticket contributor.
FIG. 7 shows how the deal feed distributor retrieves tickets from the deal feed database. At step 90, a getTicket message is sent to the distributor. A request thread checks the message and, if validated, at step 92 places the request message on a request queue. At step 94 a retrieval thread takes requests off the queue and attempts to retrieve the ticket from the database using an interface at step 96. If the ticket is successfully retrieved it is added to a response queue. If not, a blank queue is placed in the queue with an error message. At step 98 the storage results are placed on the response queue and at step 100, a response thread takes tickets of the response queue and, at step 102, if they are not blank, returns a TicketInfo message to the client. If they are blank, a ticket failure message is sent.
FIG. 8 shows how the known system is modified in accordance with an embodiment of the invention. FIG. 8 is a modification of FIG. 4. The deal feed database is modified to include a virtual deal code mappings configuration 34. This is a storage device that stores a list of virtual deal codes and the actual deal codes that map to that virtual deal code. Thus, the virtual deal code Local/MyVDC stores EBSTrader/EBSA, EBSTrader/EBSB, SPOT/EBSA and SPOT/EBSB as the mappings for that virtual deal code. The database tables are supplemented by a virtual ticket table 36 which is written to whenever a ticket is received which is from a real deal code that maps to the virtual deal code.
The manner of operation of the modified system of FIG. 8 is similar to that described with respect to the known deal feed system. In addition, when a deal ticket is received at the deal feed contributor 22, the origin of that ticket, EBSTrader/EBSA is looked up in the Virtual Deal Codes Configuration 34 to determine whether there is a virtual deal code to which the actual deal code maps. If such a virtual deal code is found, the deal, in addition to being written to the deal code, ticket and leg tables 26, 28 and 30 is also written to the virtual ticket table 36. The entry at the virtual ticket table 36 will include the virtual trading system name, for example 'Local' and the Virtual Deal Code Name, for example 'MyVDC'. A reference to the ticket in the ticket table is also included with an RSN number within the Local/MyVDC deal range and in the deal code table 30 the deal range for Local/MyVDC is updated. In the ticket table, only the reference to the virtual ticket table is stored. There is no need to store the actual ticket details a second time.
As additional deals are retrieved by the deal feed contributor they are stored against their base Trading System/Deal Code, that is their actual deal code and are referenced against a virtual deal code in the virtual ticket table if such a virtual deal code is detected in the virtual deal code mappings configuration. Thus, if for example, the deal feed contributor retrieves 10 deals from each of EBSTrader/EBSA, SPOT/EBSA, EBSTrader/EBSB and SPOT/EBSB deal codes, each in their separate deal ranges, the Local/MyVDCI virtual deal code range would be indicating a range of 40 deals and the back office system which subscribes to the output of the deal feed distributor receives all 40 actual deal code data on the Local/MyVCD output whilst perceiving a single deal code. In the case of the Reuters TOF protocol, the multiple deal codes are perceived as a single TCID.
Thus, in the system described, local deal feed outputs at each trading system on each trading floor output deal data to the deal feed contributor. As the system includes a mapping of actual deal codes to virtual deal codes, the deal feed distributor can output the deal feed data from a number of actual deal codes as a single virtual deal code. This enables a bank's back office to receive deal tickets from all trading systems on all trading floors as a single input, removing the need for large amounts of cablings used by the prior art requirement for a single feed for each deal code/trading system pair.
As the virtual deal codes described may be used in the context of an existing deal feed system, virtual deal codes may be used with all existing adapters. Thus, the embodiment described has the advantage of being easy to implement with minimal additional expense.
Existing deal feed systems are client server systems with the clients being located at banks' trading floors. Virtual deal code functionality may be included at both the deal feed client and the deal feed server. This provides complete flexibility as between the system provider and the customer as to who manages the configuration of Virtual Deal Codes. The database on existing deal feed systems merely requires reconfiguration to include a new field in the Deal Code table for referencing to a new virtual ticket table. However, the actual deal ticket is only stored once on the client and the server. The virtual deal codes are no more than references to the existing ticket stored in the database.
The configuration of virtual deal codes is very flexible enabling customers to change the mappings of actual deal codes onto a virtual deal code. Thus, deal ranges can be added and removed. There is also no limit to the number of Trading System/Deal Codes that can be created and mapped to a single virtual deal code. Banks may, if they choose, present the same set of information combined in any number of Virtual Deal Codes.
The embodiment described allows banks to receive deals, and if appropriate, associated conversations, from multiple trading systems and deal codes using any of the systems adapters, such as TOF, ASI and TOF over IP through a single socket or serial connection, by using a single deal code, irrespective of the trading system or the trading floor where the deal was done. The Deal Feed System only transmits one deal code and provides a single ticket/RSN number to the client even though multiple trading systems and/or deal codes have been mapped to a single socket or serial connection.
Various modifications to the embodiment described are possible within the scope of the invention. For example, an institution may wish to set up a number of virtual deal codes, with each virtual deal code representing a number of floors trading on a single system. Thus, a first virtual deal code may represent all floors using an EBS conversational trading system and a second code for all trading floors using an EBS anonymous matching system.
The invention is not limited to the use of virtual deal codes within the specific deal feed system described. The concept of virtual deal codes may be implemented in a variety of different ways in various different types of deal feed systems all of which are within the scope of the invention.